PROJECT SUMMARY Cortical interneurons are a diverse set of local inhibitory cells essential for proper balance of excitation and inhibition and key to brain function. Abnormal development of interneurons can lead to severe neuropsychiatric disorders (interneuropathies). Identification of the molecular pathways and cellular populations implicated in these disorders is necessary to understand their etiology and to improve our ability to predict which individuals are at risk. Work from our original grant demonstrated that the infant frontal lobe maintains a large population of migratory interneurons for several months after birth. This collection of migrating young neurons (Arc) targets many areas of the infant frontal lobe. These cells contribute importantly to the final interneuron composition of the human brain (e.g. cingulate gyrus). The human cortex, therefore, continues to receive interneurons for several months after birth, especially in areas of higher cognition implicated in neurodevelopmental disorders. Similarly, our recent evidence shows that the human amygdala continues to receive many young neurons postnatally. These observations significantly change how we view the development of the infant brain and raise the need to better understand the origins of human cortical interneurons, including those that migrate postnatally in the Arc. Young neurons in the human Arc and amygdala are postmitotic (Ki67-), supporting the hypothesis that they are not generated within these regions. The expression pattern of regional transcription factors in the Arc, suggests that they come from the developing human ventral forebrain; the Medial and Caudal Ganglionic Eminences (hMGE and hCGE). The project's overall goal is to understand how the human GE generates large numbers and diverse types of cortical interneurons by studying its development during the mid- late gestation and early postnatal life. We will determine the genetic and molecular properties of proliferative populations in the hMGE, hLGE, and hCGE using human postmortem brain samples from neonatal and infant cases (up to 6 months after birth), define how interneuron subtypes arise in the perinatal human brain. The proposed studies will identify the unique and sustained properties of human inhibitory neuron development. By using a multi-disciplinary approach (including transcriptomic, histological, and acute slice cultures), we aim to establish how interneurons are made in the human brain and provide the fundamental knowledge needed to understand their role in disease.